Biology subjects

Falkenburger, B. H.

Publications and source records attributed to Falkenburger, B. H..

3 recordsLinked to original sources

bioRxiv2024

Tissue inflammation induced by constitutively active STING is mediated by enhanced TNF signaling

Constitutive activation of STING by gain-of-function mutations triggers manifestation of the systemic autoinflammatory disease STING-associated vasculopathy with onset in infancy (SAVI). In order to investigate the role of signaling by tumor necrosis factor (TNF) in SAVI, we used pharmacological inhibition and genetic inactivation of TNF receptors 1 and 2 in murine SAVI, which is characterized by T cell lymphopenia, inflammatory lung disease and neurodegeneration. Pharmacologic inhibition of TNF signaling improved T cell lymphopenia, but had no effect on interstitial lung disease. Genetic inactivation of TNFR1 and TNFR2, however, rescued the loss of thymocytes, reduced interstitial lung disease and neurodegeneration. Furthermore, genetic inactivation of TNFR1 and TNFR2 blunted transcription of cytokines, chemokines and adhesions proteins, which result from chronic STING activation in SAVI mice. In addition, increased transendothelial migration of neutrophils was ameliorated. Taken together, our results demonstrate a pivotal role of TNFR-signaling in the pathogenesis of SAVI in mice and suggest that available TNFR antagonists could ameliorate SAVI in patients. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=170 HEIGHT=200 SRC="FIGDIR/small/591149v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@177cf0org.highwire.dtl.DTLVardef@b989dorg.highwire.dtl.DTLVardef@150a0c8org.highwire.dtl.DTLVardef@6bd42d_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice

The innate immune system can protect against certain aspects of neurodegenerative diseases, but also contribute to disease progression. Stimulator of interferon genes (STING) is activated after detection of cytoplasmic dsDNA by cGAS (cyclic GMP-AMP synthase) as part of the defense against viral pathogens, activating type I interferon and NF-kB/inflammasome signaling. In order to specifically test the relevance of this pathway for the degeneration of dopaminergic neurons in Parkinsons disease, we studied a mouse model with heterozygous expression of the constitutively active STING variant N153S. In adult mice expressing N153S STING, the number of dopaminergic neurons was smaller than in controls, as was the density of dopaminergic axon terminals and the concentration of dopamine in the striatum. We also observed alpha-synuclein pathology and a lower density of synaptic puncta. Neuroinflammation was quantified by staining astroglia and microglia, by measuring mRNAs, proteins and nuclear translocation of transcription factors. Neuroinflammatory markers were already elevated in juvenile mice, thus preceding the degeneration of dopaminergic neurons. Inflammation and neurodegeneration were blunted in mice deficient for signaling by type I interferons or inflammasomes, but not suppressed completely. Collectively, these findings demonstrate that chronic activation of the STING innate immunity pathway is sufficient to cause degeneration of dopaminergic neurons. This pathway could be targeted therapeutically.

neuroscience↗

bioRxiv2019

An engineered monomer binding-protein for α-synucleinefficiently inhibits the proliferation of amyloid fibrils

Removing or preventing the formation of -synuclein aggregates is a plausible strategy against Parkinsons disease. To this end we have engineered the {beta}-wrapin AS69 to bind monomeric -synuclein with high affinity. In cultured cells, AS69 reduced the occurrence of -synuclein oligomers and of visible -synuclein aggregates. In flies, AS69 reduced -synuclein aggregates and the locomotor deficit resulting from -synuclein expression in neuronal cells. In a mouse model based on the intracerebral injection of pre-formed -synuclein seed fibrills (PFFs), AS69 co-injection reduced the density of dystrophic neurites observed three months later. In biophysical experiments in vitro, AS69 highly sub-stoichiometrically inhibited auto-catalytic secondary nucleation processes, even in the presence of a large excess of monomer. We present evidence that the AS69--synuclein complex, rather than the free AS69, is the inhibitory species responsible for sub-stoichiometric inhibition. These results represent a new paradigm that high affinity monomer binders can be strongly sub-stoichiometric inhibitors of nucleation processes.

bioengineering↗